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Rigel’s (NASDAQ:RIGL) R788’s magnitude of blood pressure increase is being compared by physicians to Merck’s Vioxx, a rheumatoid arthritis (RA) drug which was voluntarily withdrawn from the market due to cardiac concerns, experts said.
Merck (NYSE:MRK) voluntary withdrew Vioxx in September 2004, after a study found a higher rate of heart attacks and strokes in patients taking the drug.
Dr Jacob Karsh, a rheumatologist at the Arthritis Centre Ottawa Hospital-Riverside Campus, suggested that the magnitude of the increase in blood pressure experienced by some patients in the R788 studies is comparable to the increase seen with Vioxx. The mechanism of the two RA agents, however, is extremely different, as R788 acts on SYK while Vioxx is a COX-2 inhibitor. It was evident that Vioxx’s mechanism of action clearly promoted thrombosis and heart attacks, but it is unclear if R788 actually increases more serious adverse events at this point, Karsh noted.
An increased risk of heart attacks was not apparent in data released in July from the six-month Taski2 trial. Another trial, Taski3, ran for three months. The company, however, will still need to conduct long-term safety trials to evaluate this risk, Karsh said. The first-heart attacks seen with Vioxx occurred after the first twelve-week clinical trials, he noted.
The TASKi3 study was a Phase IIb trial in patients who had failed to respond to at least one biologic treatment and did not report higher response rates in ACR-20, 50 or 70 in three months. In TASKi2, a 24% ACR-50 and 18% ACR-70 difference between the arm with R788 plus methotrexate and the placebo arm, which also included methotrexate, was observed.
In Rigel’s TASKi3 trial - hypertension and diarrhea - were the most clinically relevant adverse events. Using a last observation carry forward methodology, the mean increase in blood pressure from baseline at three months was 3.2 mmHG to 3.6 mmHg for the 100 mg bid dose group.
In patients with inadequate response to anti-TNF biologics, approximately 17% of patients on the 100mg bid dose group had their blood pressure medication adjusted or initiated - compared to 8% on placebo. In TASKi2, 14% of patients on the 100mg dose had hypertension - compared to 5% on placebo. In addition, 14% of patients on the 100mg dose required a dose reduction.
Dr Charles Malemud, a professor of medicine and anatomy at the Case Western Reserve University School of Medicine, agreed that R788’s increase in blood pressure draws parallels with Vioxx and Bextra, another COX-2 inhibitor that Pfizer withdrew from the market. RA experts and regulatory agencies are concerned about any agent that increases blood pressure, Malemud noted. “We are affecting factors galore by this mechanism of action,” he said.
Dr Ed Fudman, an investigator who participated in both the TASKi2 and TASKi3 studies, said physicians were very aggressive in treating the elevation in blood pressure in patients who saw a rise. There were some patients who discontinued the trials due to an elevation in blood pressure, but there are always some patients who drop-out, Fudman said. He noted that one patient among the 12 to 15 enrolled at his site discontinued due to this adverse event. Anti-diuretics and ACE inhibitors could be used to manage the hypertension, he added. He noted that he does not believe that the side effects are concerning and that they can be controlled with anti-diuretics.
Dr Raul Rodriguez, executive vice president and chief operating officer at Rigel, said the increase in blood pressure seen with R788 should not draw a comparison with Vioxx. R788 has a completely different mechanism of action, he stressed, as it is a syk-kinase inhibitor, and comparisons should not be drawn.
It is unfair to call the elevation in blood pressure seen with R788 ”hypertension;” it is just an increase in blood pressure, Rodriguez said. The patients who experienced an increase in blood pressure are individuals who are predisposed to having this side effect, he said. Patients who developed high blood pressure were treated with ACE inhibitors, which were able to control this adverse event, he added.
Future trials will not recruit patients predisposed to developing this side effect, Rodriguez added.
“There has been a 4 millimeter increase risk in blood pressure associated with Rigel’s R788, and this leaves room for long-term safety trials,” said Dr David Shearer, the chief medical officer and vice president of clinical operations at Integrated Clinical Trial Services. Many questions arise about the way the cardiovascular trials are mandated, but there is agreement that the primary endpoint of a safety study should examine a drug’s effect on a composite hard endpoint of stroke, myocardial infarction and cardiovascular death, Shearer said.
Shearer, a consultant who designs clinical trials, noted that the verdict is still out on whether Rigel will need to conduct these trials pre- or post-approval. Other questions will be which treatment comparators should be used, and how the other cardiovascular risk factors should be managed, he noted.
Dr Norman Gaylis, a rheumatologist at Arthritic and Rheumatic Disease Specialties who has been an investigator on several clinical trials, said the comparison in adverse events to Vioxx was entirely reasonable and is an appropriate comparison at this juncture. This is ”absolutely” a chief concern as Rigel moves onto Phase III trials, he said.
A clinical investigator on numerous RA drugs said R788 at this point in development reminds him of Vioxx. The hypertension numbers are similar to Vioxx’s, he noted, citing the rise in diastolic blood pressure. With the side effects of hypertension seen so far with R788, in light of the agent’s modest efficacy, he said he would not feel comfortable prescribing additional medicine - namely anti-hypertensive agents - to patients just so they can use this drug.
A consultant who specializes in rheumatology said Rigel’s R788 hypertension side effect profile seems to highly concerning. The drug has drawn some comparisons to Vioxx, which is troublesome, as this drug was ultimately withdrawn from the market. More importantly, the consultant remained concerned about R788’s hypertension profile if used in a longer-term setting.
The hypertension with R788 is a concern, but the degree to which the agent affects hypertension is unclear, said Dr Larry Brent, a rheumatologist at Albert Einstein Medical Center, Einstein Arthritis Center in Philadelphia. The FDA will certainly need the company to conduct long-term cardiovascular studies to rule out any potential side effects, Brent noted. If the agent is approved, it will only be used as a second or third line therapy, he said.
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